High Plus Low Dose Radiation Strategy in Combination with TIGIT and PD1 Blockade to Promote Systemic Antitumor Responses.

Hampartsoum B Barsoumian,Duygu Sezen,Maria A Cortez,Hari Menon,Mark Wasley,Liangpeng Yang,Kewen He,Roshal R Patel,Yun Hu,Ethan Hsu,Ahmed I Younes,Nahum Puebla-Osorio,James W Welsh

doi:10.3390/cancers14010221

Abstract

Simple SummaryThis study combines a novel strategy of radiotherapy that utilizes high- and low- dose radiation with immune oncology agents (anti-TIGIT and anti-PD1 monoclonal antibodies) in order to overcome the inhibitory tumor stroma and battle tumors systemically. The findings from this work will impact how checkpoint inhibitors are delivered to maximize their efficacy. Tumors deploy various immune-evasion mechanisms that create a suppressive environment and render effector T-cells exhausted and inactive. Therefore, a rational utilization of checkpoint inhibitors may alleviate exhaustion and may partially restore antitumor functions. However, in high-tumor-burden models, the checkpoint blockade fails to maintain optimal efficacy, and other interventions are necessary to overcome the inhibitory tumor stroma. One such strategy is the use of radiotherapy to reset the tumor microenvironment and maximize systemic antitumor outcomes. In this study, we propose the use of anti-PD1 and anti-TIGIT checkpoint inhibitors in conjunction with our novel RadScopal technique to battle highly metastatic lung adenocarcinoma tumors, bilaterally established in 129Sv/Ev mice, to mimic high-tumor-burden settings. The RadScopal approach is comprised of high-dose radiation directed at primary tumors with low-dose radiation delivered to secondary tumors to improve the outcomes of systemic immunotherapy. Indeed, the triple therapy with RadScopal + anti-TIGIT + anti-PD1 was able to prolong the survival of treated mice and halted the growth of both primary and secondary tumors. Lung metastasis counts were also significantly reduced. In addition, the low-dose radiation component reduced TIGIT receptor (PVR) expression by tumor-associated macrophages and dendritic cells in secondary tumors. Finally, low-dose radiation within triple therapy decreased the percentages of TIGIT+ exhausted T-cells and TIGIT+ regulatory T-cells. Together, our translational approach provides a new treatment alternative for cases refractory to other checkpoints and may bring immunotherapy into a new realm of systemic disease control.

Highlights

Despite current advances in cancer immunotherapy with checkpoint inhibitors such as anti-PD1, anti-PD-L1, and anti-CTLA-4, most patients do not realize the full benefit(s) due to intrinsic or acquired resistance
Others reported the occurrence of abscopal responses in non-small-cell lung cancer (NSCLC) patients treated with radiotherapy and anti-CTLA-4, accompanied by the production of IFN-β cytokine [4]
Primary tumors were treated with L-XRT (2Gy total, divided over two fractions of 1Gy each) and systemic α-TIGIT; H-XRT was found superior to L-XRT in improving overall survival when compared to α-TIGIT alone (α-TIGIT vs. L-XRT + α-TIGIT, p = 0.0861; α-TIGIT vs. H-XRT + α-TIGIT, p = 0.0058)

Summary

Introduction

Despite current advances in cancer immunotherapy with checkpoint inhibitors such as anti-PD1, anti-PD-L1, and anti-CTLA-4, most patients do not realize the full benefit(s) due to intrinsic or acquired resistance. This is a challenge in lung cancer, which is the second-most-common malignancy in the world. We are beginning to understand that XRT helps release neo-antigens after cell death, upregulate MHC-I molecules [1], and prime T-cells. All of these functions may yield benefits in generating abscopal responses, which have eluded clinicians for decades. The addition of L-XRT modulated the tumor microenvironment (TME) and its associated stroma to allow better infiltration of effector immune cells and enhanced the response to checkpoint inhibitors [6,7]

Methods

Results

Conclusion